PMS is a very common problem that affects millions of young women during their reproductive lives, disrupting their emotional and physical well being. It is widely recognized as a recurrent, cyclical disorder related to the latter half of the menstrual cycle, subsiding with the onset of menses. The syndrome is characterized by a complex group of signs and symptoms that may include depression, mood swings, irritability, fatigue, abdominal discomfort and changes in appetite. Although many women experience only mild symptoms, as many as 30-50% suffer from troublesome symptoms. Surveys indicate that approximately 5% of North American women consider their symptoms to be severe enough to have a substantially negative impact on their health and social well being. It has been suggested that women in this latter group be defined as having Premenstrual Dysphoric Disorder (PMDD).
There is no one established therapy for PMS. A variety of treatments have been proposed over the years including lifestyle and dietary modifications, herbal remedies, hormonal therapies and pharmacologic interventions. The majority have proven ineffective or only temporizing, while other treatments have proven scientific efficacy. Some popular methods of treatment that have failed scientifically rigorous evaluation include progesterone therapy, monamine oxidase inhibitors, bromocriptine and evening primrose oil. Proven treatments of PMS include calcium supplementation, the selective serotonin receptor reuptake inhibitors (SSRIs) and the gonadotropin releasing hormone agonists. For some women, recommending lifestyle changes or a daily pharmacologic regimen is not satisfactory for a natural biological process.
Evidence has now demonstrated that PMS is associated with a calcium and vitamin D deficiency state that is clinically unmasked during the latter half of the menstrual cycle when estradiol and progesterone predominate. U.S. Pat. Nos. 4,946,679, 5,354,743, 6,228,849 with articles Thys-Jacobs (Thys-Jacobs S, Ceccarelli S I Bierman A, Weisman H, Cohen M A, Alvir J A. Calcium Supplementaion in premenstrual syndrome. J Gen Intern Med 1989; 4:183-189; Thys-Jacobs S, Alvir M A J. Calcium regulating hormones across the menstrual cycle: evidence of a secondary hyperparathyroidism in women with PMS. J Clin Endocrinol Metab 1995; 80: 2227-2232; Thys-Jacobs S, Starkey P, Fratarcangelo P, Bernstein D, Tian J. Calcium Carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Am J Obstet Gynecol 1998;179:444-52) showed that elemental calcium and vitamin D significantly reduced PMS symptomatology. The majority of PMS symptoms such as irritability, depression, anxiety, social withdrawal, headache, and abdominal cramps are alleviated with calcium supplementation. Calcium has been demonstrated to result in a beneficial clinical response in the treatment of premenstrual symptomatology in a number of studies and has been shown to significantly benefit all 4 major categories of PMS (emotional or negative affect symptoms, bloated or water retention symptoms, food cravings and pain symptoms) reducing overall symptoms by 50%. In the largest of these clinical trials, calcium was compared to placebo. Seven hundred and twenty healthy premenopausal women between the ages of 18 and 45 years were recruited nationally in the United States and screened over 2 menstrual cycles for moderate to severe cyclically recurring symptoms. Elemental calcium, 1200 mg per day in the form of calcium carbonate effectively resulted in an overall 48% reduction in total symptom scores compared to placebo within 3 months of therapy. Daily calcium (1500 mg) and vitamin D (1600 IU) therapy as well for 3 to 4 months has also been documented to alleviate symptoms (Thys-Jacobs S, Alvir M A J. Calcium regulating hormones across the menstrual cycle: evidence of a secondary hyperparathyroidism in women with PMS. J Clin Endocrinol Metab 1995; 80: 2227-2232)
Calcium has been demonstrated in animal investigations as well as in human studies to be dynamically related to both the estrus and menstrual cycles. Fluctuations of the calcium regulating hormones (parathyroid hormone [PTH], 25 hydroxyvitamin D [25OHD], 1,25 dihydroxyvitamin D and ionized calcium) across the menstrual cycle may explain many of the features of PMS. Evidence supports cyclical changes in the calciotropic hormones in a number of investigations involving healthy premenopausal women. In 1978, Pitkin and colleagues (Pitkin R, Reynolds W A, Williams G A, Hargis G K. Calcium regulating hormones during the menstrual cycle. J Clin Endocrinol Metab 1978; 47: 626) measured calcium, the calcium regulating hormones and calcitonin across the menstrual cycle in 7 healthy premenopausal women. They were the first to report that parathyroid hormone (PTH) and the biologically active form of vitamin D-1,25 dihydroxyvitamin D progressively increased in concentration through the follicular phase of the cycle in human studies. Subsequently, both Gray et al and Tjellesen et al (Gray T K, et al. Fluctuation of serum concentration of 1,25 dihydroxyvitamin D during the menstrual cycle. Am J Obstet Gynecol. 1982; 144:880.) noted periovulatory elevations of 1,25 dihydroxyvitamin D in premenopausal women. A similar pattern of the menstrual cyclicity of the calcium-regulating hormone (total and ionized calcium, intact PTH, 1,25 dihydroxyvitamin D [1,25(OH)2D], 25 hydroxyvitamin D [25OHD]) was noted in a study involving women with PMS compared to asymptomatic controls, with both total calcium and ionized calcium significantly varied across the three phases of the menstrual cycle (Thys-Jacobs S, Alvir M A J. Calcium regulating hormones across the menstrual cycle: evidence of a secondary hyperparathyroidism in women with PMS. J Clin Endocrinol Metab 1995; 80: 2227-2232).
Alterations in calcium homeostasis have long been associated with many affective disturbances. Hypocalcemia (abnormally low calcium concentrations) has been associated with irritability, anxiety and mania; while hypercalcemia (abnormally elevated calcium concentrations) as typified by primary hyperparathyroidism has been noted in some patients with depression. PMS shares many of the features of depression, anxiety, the dysphoric states and is remarkably similar to those symptoms associated with hypocalcemia and indeed daily calcium treatment has been found to alleviate PMS. Calcium is an essential intracellular and extracellular cation. Extracellular calcium is required to maintain normal biologic functioning of the nervous system (neuronal conductance and synaptic transmission of acetylcholine) as well as many other systems. In the brain, the synthesis of the neurotransmitters serotonin, norepinephrine and acetylcholine is dependent on intracellular calcium concentrations.
Vitamin and mineral preparations are commonly administered to treat specific medical conditions or as general nutritional supplements. Micronutrients are elements or compounds that are present in foods in small or trace amounts and include vitamins, minerals, or other elements. The macronutrients comprise carbohydrates, fats, and proteins, that supply nutrients and calories. The primary source of all nutrients is of course food. However, the majority of people do not meet the Recommended Dietary Allowance—RDA of the foods containing these essential compounds and elements. Thus vitamin and mineral supplementation has become a recognized method of meeting accepted medical and health standards.
Vitamin D is a fat soluble vitamin that is rarely found naturally in food. It is not a true vitamin, but is a steroid prohormone that is produced in the skin by ultraviolet sunlight and converted by a series of hydroxylations to a biologically active steroid hormone metabolite (M. Peacock. “Effect of calcium and vitamin D insufficiency on the skeleton. Osteoporosis Int. Suppl 8: S45-S51.(1998); Reinhold Vieth. “Vitamin D supplementation, 25-hydroxyvitamin D concentrations and safety.” Am J Clin Nutrition, vol 69, pp. 842-56 (1999) (herein Peacock M; Vieth R). Vitamin D is a major regulator of calcium homeostasis and bone metabolism. However, only recently has it been hypothesized (R Vieth. “Vitamin D supplementation, 25-hydroxyvitamin D concentrations and safety.” Am J Clin Nutrition, vol 69, pp. 842-56. (1999) that ingestion of adequate concentrations of vitamin D that maintain vitamin D in the sufficiency range can result in superior bone health and vitality. There have been many reported benefits of vitamin D such as in the prevention of osteomalacia, osteoporosis, breast and colon cancer, osteoarthritis progression and hypertension. Recent evidence suggests that vitamin D may have anti-inflammatory and immunosuppressive effects. In one review, (PC van de Kerkhof. “Biological activity of vitamin D analogues in the skin, with special reference to antipsoriatic mechanisms” Brit J Derm. Vol 132. pp 675-82. (1995)), active vitamin D was noted to modulate epidermal growth, keratinization and inflammation and proved effective in the treatment of the skin disease, psoriasis. Calcitriol, an active metabolite of vitamin D was noted to decrease keratinocyte proliferation, normalize keratinocyte differentiation and decrease immune activation in plaques (I Lu et al. “Modulation of epidermal differentiation, tissue inflammation, and T-lymphocyte infiltration in psoriatic plaques by topical calcitriol”. J Cutaneous Pathology. Vol 23, pp 419-30. (1996)). Active vitamin D appeared to suppress immune and keratinocyte activation. Another study by Matsuyama and colleagues (W Matsuyama. “Idiopathic Hypoparathyroidism with fungal seminal inflammation. Internal Medicine.” 36: 113-7; 1997) suggested that active vitamin D may possess immunological effects. Abnormalities of calcium regulation with low calcium and parathyroid hormone concentrations as described in a patient with idiopathic hypoparathyroidism resulted in fungal infections that were successfully treated with the anti-fungal treatment fluconazole only when the patient was administered active vitamin D therapy. Muller et al. reported that proliferation of T-cells and their release of cytokines such as IL-2 and interferon gamma were also suppressed by active vitamin D. (K Muller et al. “1,25dihydroxyvitamin D3 as a natural regulator of human immune functions”. Journal Investigative Dermatology. Vol 1, pp. 68-71 (1996)). Vitamin D insufficiency defined as a serum 25 hydroxyvitamin D concentration below 35 ng/ml can result in reduced calcium supplies, accelerated bone turnover and suboptimal bone mass and mineralization (Peacock M.). Levels of 25 hydroxyvitamin D above 9-10 ng/ml were for many years believed to be sufficient and optimal for calcium homeostasis and bone health with the RDA (recommended dietary allowance) at 400 IU corresponding to a safe and adequate intake. Because vitamin D is lipid soluble and potentially toxic, oral intakes of vitamin D greater than 1000 IU have not been advised. One report cites that ingestion of parent vitamin D, cholecalciferol, is safe at daily doses of 2000 IU up to 10,000 IU daily with toxicity occurring at doses of 40,000 IU daily (Vieth R). Another investigation by Heaney and colleagues (Am Journal Clin Nutr 2003; 77:2040210) reported that 10,000 IU of vitamin D3 daily for 5 months was safe. Attaining a 25 hydroxyvitamin D concentration above 40 mg/ml may involve an intake of more than 2000 IU daily.
Calcium has been shown to be particularly effective in improving health. It is an essential mineral nutrient that is necessary on a daily basis for numerous key physiologic functions in the body, including nerve, muscle, skin, endocrine functions acting as an important second messenger. Deficiencies of calcium can have broad ranging adverse effects on many tissues and may manifest clinically as irritability, muscle spasm, myalgias, fatigue, anxiety and depression. Adequate dietary calcium intake has been shown to reduce bone resorption, osteoporosis and fracture risk. Chronic low dietary calcium intake results in low bone mass in many animal investigations, while calcium supplementation leads to increased bone mass (Peacock M). Calcium is required in supporting the bone formation phase of bone remodeling and is essential in bone growth, in optimizing peak bone mass and in the mineralization of the skeleton (B D Hughes. “Effect of calcium and vitamin D supplementation on Bone Mineral Density in men and women 65 years of age or older” New England Journal of Medicine. Vol 337. pp. 670-6. (1997)). Inadequate and low calcium intake can influence optimum fracture healing and probably healing in general. (T Kubo. Etal. “Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet.” Journal Steroid Biochemistry & Molecular Biology. Vol 68. pp. 197-202. (1999). “Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet.” Journal Steroid Biochemistry & Molecular Biology. 1999 Vol 68. pp. 197-202). The current DRI (Dietary Reference Intake) for adults younger than 50 years is 1000 mg of elemental calcium daily; and for adults older than 50 the DRI is 1500 mg daily of calcium.
There exists a need for a nutritional supplement that supplies appropriate and effective amounts of calcium and vitamin D at the time of symptom occurrence instead of continuous therapy for those who suffer from premenstrual syndrome, panic attacks and postpartum depression.
However, even something as natural as daily calcium and vitamin D supplementation in the treatment of PMS poses a burden to those who are resistant to a daily preventative regimen, when symptoms only occur for a few days a month. In the past few years, the concept of intermittent therapy for the treatment and management of PMS instead of continuous therapy has been studied with the selective serotonin reuptake inhibitors. Miner and colleagues in 2002 randomized women with PMS to fluoxetine bolus dosing and found that higher doses administered once or twice during the luteal phase of the cycle was effective in reducing symptomatology. This has never been shown to date for calcium and vitamin D therapy for the immediate relief of PMS symptoms.
In contrast to U.S. Pat. No. 6,228,849, which describes a method for the treatment of PMS with a daily combination of calcium and vitamin D, there exists a need for an intermittent or bolus nutritional supplement that supplies an effective amount of vitamin D and calcium at the time of immediate symptom occurrence to those who experience recurrent, though intermittent PMS symptoms, panic attacks, anxiety and depression.